This invention relates to method and apparatus for delivering a biologically active compound to a biological environment in a controlled fashion.
The more precise control of the release of orally administered drugs has long been sought. In particular, it is desired that an orally administered drug or other biologically active compound be released only upon the occurrence of a desired environmental condition within a biological system. For example, it may be desired that a biologically active compound be released only in the intestines rather than being released as the material passes through the mouth and stomach. Prior art controlled release techniques typically result in initiation and/or continuation of controlled release as a function of time after ingestion.
An example of a controlled release oral delivery system is the so-called osmotically-controlled delivery system. See, for example, Wang et al., U.S. Pat. No. 5,413,572; Theeuwes et al., U.S. Pat. No. 3,845,770; Wang, U.S. Pat. No. 5,312,390; Eckenhoff et al., U.S. Pat. No. 4,474,575; Place et al., U.S. Pat. No. 5,147,654; Eckenhoff et al., U.S. Pat. No. 4,539,004; and Magruder et al., U.S. Pat. No. 4,777,049. The technology disclosed in these patents utilizes the osmotic pressure resulting from concentration gradients to expel a biologically active substance into the body. In some embodiments, the osmotic pressure moves a moveable partition to effect drug release. Wang et al., in the '572 patent, also teaches the use of a hydrogel which expands when contacted with water, the expansion serving to expel the biologically active material.
Osmotic pressure based systems have the shortcoming that they depend on flux and pressure for their operation. It is known that a desirable drug delivery system should be independent of both flux and pressure. In addition, an osmotic pressure based system has release kinetics that are highly dependent on orifice size. The osmotic pumps of the prior art operate on the principle of net flux of water across a semipermeable membrane into a compartment that contains the osmotic driving agent. The rate of flux is controlled by the water permeable membrane characteristics and the difference in osmotic and hydrostatic pressure between the compartment containing the osmotic driving agent and the outside of the device. The flux J of water may be represented as J=K.multidot.A.multidot.(.sigma..multidot..DELTA..pi.-.DELTA.P) where K is the permeability of the membrane, A is the membrane's surface area, .sigma. is the osmotic coefficient of the membrane, .DELTA..pi. is the osmotic pressure and .DELTA.P is the hydrostatic pressure. See, Theeuwes et al., "Principles of the Design and Operation of Generic Osmotic Pumps for the Delivery of Semisolid or Liquid Drug Formulations," Annals of Biomed. Eng., 4(343), 1976.
As stated above, the prior art osmotic systems are also very sensitive to the size of the delivery orifice. See, Theeuwes et al., "Elementary Osmotic Pump," J. Pharm. Sci., 64(1987), 1975. The orifice size must be small so as to minimize diffusion through the orifice and yet still be sufficiently large to minimize hydrostatic pressure inside the system that would affect the zero-order release kinetics. Further, the release kinetics in osmotic systems are independent of pH and motility of the gastrointestinal tract. See, Fara et al., "Osmotic Pumps in Drug Delivery Devices--Fundamentals and Applications," Praveen Tyle, ed., Marcel Dekker, Inc., p137 (New York).
Other systems for non-continuous delivery of drugs, for example, the Pulsncap system are known in the prior art. In this system there is a limiting osmotic pressure which, when achieved, pushes out a cap to begin drug release.
Reference is also made to the prior art connection of an osmotic system to a syringe-like system to provide an external continuous IV/IM/SQ infusion. See, U.S. Pat. No. 3,604,417 and Urquhart et al., "Rate-Controlled Delivery Systems in Drug and Hormone Research," Ann. Rev. Pharmacol. Toxicol., 24(199), 1984.
In none of the prior art delivery systems is there initiation and continuation of release upon the occurrence of an environmental condition such as pH which changes from place to place within the body.
As discussed in co-pending application Ser. No. 08/413,409 of which this application is a continuation-in-part, volumetric change phenomena have been observed in three-dimensional, permanently crosslinked polymer gel networks. As an external environmental condition (e.g., temperature, solvent composition, pH, electric field, light intensity and wavelength, pressure, ionic strength, osmolarity) is changed, the polymer gel network contracts and/or expands in volume. The volume of such a gel may, under certain circumstances, change reversibly by a factor as large as several hundred when the gel is presented with a particular external condition (i.e., the gel is a "responsive" gel; see, for example, Tanaka Phys. Rev. Lett. 40(820), 1978; Tanaka et al., Phys. Rev. Lett. 38(771), 1977; Tanaka et al., Phys. Rev. Lett. 45(1636), 1980; Ilavsky, Macromolec. 15(782), 1982; Hrouz et al., Europ. Polym. J 17, p361, 1981; Ohmine et al., J. Chem. Phys. 8(6379), 1984; Tanaka et al., Science 218(462), 1982; Ilavsky et al., Polymer Bull. 7(107), 1982; Gehrke "Responsive Gels: Volume Transitions II", Dusek (ed.), Springer-Verlag, New York, p81-144, 1993; Li et al., Ann. Rev. Mat. Sci. 22(243), 1992; and Galaev et al., Enzyme Microb. Technol. 15(354), 1993, each of which is incorporated herein by reference).
As disclosed in the co-pending application Ser. No. 08/413,409 referred to above, a number of significant studies have demonstrated the potential of responsive gels in solutes/solvent separations (see, for example, Kussler, U.S. Pat. 4,555,344) and in biomedical applications (see, for example, Hoffman, U.S. Pat. 4,912,032). Synthesis of a gel may utilize monomers and/or polymers whose toxicologic hazard characteristics are ill defined (e.g., n-isopropylacrylamide, NIPA and related acrylic monomers, polymers and co-polymers). Further, synthesis of a gel may use crosslinkers known to be toxic (e.g., divinylsulfone (DVS), glutaraldehyde, divinylbenzene, n-n-methylenebisacrylamide, and the like). Harsh and Gehrke (J. Control. Rel. 17(175), 1991, incorporated herein by reference) have created certain gels based on cellulose ether polymeric precursor materials. These cellulosic ether precursor materials are currently acceptable by the U.S. Food and Drug Administration, but these gels were made using toxic DVS crosslinkers that are not FDA acceptable. One way to avoid use of toxic chemical crosslinkers is by use of radiation crosslinking. This method is problematic inasmuch as it may lead to the presence of unreacted monomers.
As disclosed in the co-pending application Ser. No. 08/413,409, a suitable gel material for use in a biological environment is a crosslinked, responsive polymer gel network comprising polymer chains interconnected by way of multifunctional crosslinkers. The polymer chains and crosslinkers have a known acceptable toxicological profile, hereinafter referred to as "KATP." Another suitable material is a crosslinked, responsive polymer gel network comprising polymer chains interconnected by way of KATP crosslinkages. A further suitable material is a crosslinked, responsive polymer gel network having polymer chains interconnected by way of a crosslinker in which each of the polymer crosslinkers is obtainable from a precursor that is used in a process for making material that has a KATP. These gels have the characteristic that, when leached, the leachate from the network also has a KATP as well as any residual elements in the network. The gel solvent may also have a KATP.